High Production Volume (HPV) Challenge Program

Data Analysis and Test Plan

For
Phenol, 2,4,6-tris[(dimethylamino)methyl]-
Prepared by:
Air Products and Chemicals, Inc.
7201 Hamilton Boulevard
Allentown, PA 18195
Submitted: December 2003
201-15125A
Table of Contents
1.0 INTRODUCTION ................................................................................................................................................. 2
2.0 EVALUATION OF DATA .................................................................................................................................. 2
2.1 Physico-chemical Data.............................................................................................................................2
2.1.1 Melting Point .............................................................................................................................2
2.1.2 Boiling Point ..............................................................................................................................2
2.1.3 Vapor Pressure ..........................................................................................................................2
2.1.4 Partition Coefficient .................................................................................................................2
2.1.5 Water Solubility ........................................................................................................................2
2.1.6 Summary of Physico-chemical Data .....................................................................................2
2.2 Environmental Fate and Biodegradation Data .....................................................................................2
2.2.1 Photodegradation ......................................................................................................................2
2.2.2 Hydrolysis ..................................................................................................................................2
2.2.3 Biodegradation ..........................................................................................................................3
2.2.4 Transport/Distribution..............................................................................................................3
2.2.5 Summary of Environmental Fate and Biodegradation Data..............................................3
2.3 Ecotoxicology Data ..................................................................................................................................3
2.3.1 Acute Toxicity to Fish..............................................................................................................3
2.3.2 Acute Toxicity to Aquatic Invertebrates...............................................................................3
2.3.3 Toxicity to Aquatic Plants .......................................................................................................4
2.3.4 Summary of Ecotoxicology Data ...........................................................................................4
2.4 Health Effects Data...................................................................................................................................4
2.4.1 Acute Health Effects ................................................................................................................4
2.4.1.1 Acute Oral Toxicity ..................................................................................................4
2.4.1.2 Summary of the Acute Toxicological Effects ......................................................4
2.4.2 Genetic Toxicology Effects.....................................................................................................4
2.4.2.1 Bacterial Gene Mutation Assay..............................................................................4
2.4.2.2 In Vitro Chromosomal Aberration Assay.............................................................4
2.4.2.3 Summary of Genetic Toxicology Effects .............................................................4
2.4.3 Repeated Dose Health Effects ................................................................................................5
2.4.3.1 Systemic Oral Toxicity ............................................................................................5
2.4.3.2 Reproductive and Developmental Toxicity ..........................................................5
2.4.3.3 Summary of Systemic, Reproductive and Developmental Toxicity Effects ..5
3.0 CONCLUSIONS .................................................................................................................................................... 5
4.0 REFERENCES ....................................................................................................................................................... 7
LIST OF TABLES
Table 1- HPV Data Requirements/Critical Studies for Phenol, 2,4,6-tris[(dimethylamino)methyl]- ........................6
Phenol, 2,4,6-tris[(dimethylamino)methyl]- 1
1.0 INTRODUCTION
Phenol, 2,4,6-tris[(dimethylamino)methyl]- is a Mannich base that is used as a delayed-action gelation catalyst
for rigid foams, as a curing agent and as a tertiary amine activator for epoxy resins cured with a wide variety of
hardener types. Phenol, 2,4,6-tris[(dimethylamino)methyl]- has the following structure:
HO
N
N
N
Air Products and Chemicals, Inc. has committed to provide basic chemistry, environmental fate, ecotoxicity and
health effects information on phenol, 2,4,6-tris[(dimethylamino)methyl]- (CAS 90-72-2) listed under the
Environmental Protection Agency (EPA) High Production Volume (HPV) Chemical Challenge Program. By
participating in this voluntary program, Air Products and Chemicals, Inc., agreed to assess the adequacy of
existing data; prepare summaries of the data characterizing the chemical; determine data needed to fulfill the
HPV data requirements; and design and submit a test plan to satisfy these testing requirements.
2.0 EVALUATION OF DATA
2.1 Physico-chemical Data
2.1.1 Melting Point: -20 C (-4 F) [Ref. 1]
2.1.2 Boiling Point: started to decompose at approximately 156 C (313 F) [Ref. 2]
2.1.3 Vapor Pressure: 7.5 x 10
-2
Pa @ 25C (5.6 x 10
-4
mm Hg) [Ref. 3]
2.1.4 Partition Coefficient: log Pow = -0.660 at 21.5C [Ref. 4]
2.1.5 Water Solubility: >85% w/w (>850 g/l) at 200.5C [Ref. 5]
2.1.6 Summary of Physico-chemical Data
Scientifically reliable data exists for all SIDS physico-chemical endpoints. No additional testing is
recommended.
2.2 Environmental Fate and Biodegradation Data
2.2.1 Photodegradation:
Estimation Programs Interface for Microsoft Windows (EPIWIN V3.10, U.S. Environmental
Protection Agency, Office of Pollution Prevention and Toxics, Washington, D.C.), Atmospheric
Oxidation Program (v1.90) modeling component was used to calculate the rate of photodegradation
for phenol, 2,4,6-tris[(dimethylamino)methyl]-. The half-life was calculated to be 0.042 days (or
approx. hour), assuming the reaction occurred over a 12-hour day with an average atmospheric
concentration of 1.5x 10
6
OH/cm
3
[Ref. 6].
2.2.2 Hydrolysis:
For hydrolysis reactions to occur, there must be an electrophilic carbon atom, which is attacked by
oxygen, and a leaving group, which departs from the attacked carbon atom. The most
electropositive carbon in the phenol, 2,4,6-tris[(dimethylamino)methyl]- molecule is the carbon
attached to the phenolic OH group due to the electron withdrawing effect of the phenolic OH group.
Phenol, 2,4,6-tris[(dimethylamino)methyl]- 2
The hydrolysis reaction of phenol, 2,4,6-tris[(dimethylamino)methyl]- if it were to occur, would
occur by attack of water or OH at the carbon attached to the phenolic OH group. The product of
such a reaction would be phenol, 2,4,6-tris[(dimethylamino)methyl]- itself, indicating that there
would be no net hydrolysis reaction.
Phenol, 2,4,6-tris[(dimethylamino)methyl]- would be hydrolytically stable under the conditions of
the OECD hydrolysis test (OECD Guideline 111), and laboratory testing is not required.
2.2.3 Biodegradation:
Phenol, 2,4,6-tris[(dimethylamino)methyl]- degraded approximately 4% in 28 days in the Closed
Bottle test (OECD 301D). Phenol, 2,4,6-tris[(dimethylamino)methyl]- is therefore not readily
biodegradable [Ref. 7].
2.2.4 Transport/Distribution:
The Level III fugacity model (from EPIWIN V3.10, US EPA) was used for predicting partitioning of
phenol, 2,4,6-tris[(dimethylamino)methyl]- among air, water, soil and sediment compartments. The
following are the concentration results using a soil K
oc
of 0.0897 as calculated by the model and a
log K
ow
of -0.66 as determined through octanol water partition coefficient testing [Ref. 8]:
- Air <0.01%
- Water 51.9%
- Soil 48%
- Sediment <0.1%
2.2.5 Summary of Environmental Fate and Biodegradation Data
Scientifically reliable data exists for most SIDS environmental fate and biodegradation endpoints.
No additional testing is recommended.
2.3 Ecotoxicology Data
2.3.1 Acute Toxicity to Fish:
Phenol, 2,4,6-tris[(dimethylamino)methyl]- was tested in both rainbow trout and carp [Ref. 9].
Rainbow trout (Salmo gairdneri) were exp osed for 96 hours to concentrations of 0, 140, 180, 240,
280, and 320 mg/l of phenol, 2,4,6-tris[(dimethylamino)methyl]- in a static system. Ten fish were
exposed at each concentration. The 24- and 96-hour LC
50
values (concentration causing 50% of the
fish to die) were determined. The 24-hour LC
50
value was 222 mg/l with a 95 percent confidence
interval of 174 to 283 mg/l. The 96-hour LC
50
value was >180 mg/l but <240 mg/l. The 96-hour
LC
100
value was 240 mg/l. The 96-hour No Observed Effect Level (NOEL) was 180 mg/l.
Carp (Cyprinus carpio) were exposed for 96 hours to concentrations of 0, 140, 240, 320, and 420
mg/l of phenol, 2,4,6-tris[(dimethylamino)methyl]- in a static system. Ten fish were exposed at each
concentration. The 24- and 96-hour LC
50
values were determined. The 24-hour LC
50
value was 249
mg/l with a 95 percent confidence interval of 204 to 305 mg/l. The 96-hour LC
50
value was 175
mg/l with a 95 percent confidence interval of 131 to 235 mg/l. The 96-hour LC
100
value was 240
mg/l. The 96-hour NOEL was 140 mg/l.
These results indicate that phenol, 2,4,6-tris[(dimethylamino)methyl]- is practically nontoxic to fish.
2.3.2 Acute Toxicity to Aquatic Invertebrates:
Phenol, 2,4,6-tris[(dimethylamino)methyl]- was tested in both mud crabs and grass shrimp [Ref. 10].
Mud crabs (Neopanope texana) were exposed for 96 hours to concentrations of 0, 320, 420, 560,
750, and 1000 mg/l. Ten mud crabs were exposed at each concentration. The 24- and 96-hour LC
50
values were determined. The 24- and 96-hour LC
50
values were >750 mg/l but <1000 mg/l. The 96-
hour LC
100
value was 1000 mg/l. The 96-hour NOEL was 750 mg/l.
Phenol, 2,4,6-tris[(dimethylamino)methyl]- 3
Grass shrimp (Palaemonetes vulgaris) were exposed for 96 hours to concentrations of 0, 320, 420,
560, 750, and 1000 mg/l. Ten shrimp were exp osed at each concentration. The 24- and 96-hour
LC
50
values were determined. The 24-hour LC
50
value was >750 mg/l but <1000 mg/l. The 96-hour
LC
50
was 718 mg/l with a 95 percent confidence interval of 524 to 984 mg/l. The 96-hour NOEL
was 560 mg/l.
These results indicate that phenol, 2,4,6-tris[(dimethylamino)methyl]- is practically nontoxic to
aquatic invertebrates.
2.3.3 Toxicity to Aquatic Plants:
Phenol, 2,4,6-tris[(dimethylamino)methyl]- has not been tested in algae.
2.3.4 Summary of Ecotoxicology Data
Phenol, 2,4,6-tris[(dimethylamino)methyl]- is practically nontoxic to fish and aquatic invertebrates.
Scientifically reliable data exists for these two SIDS ecotoxicity endpoints. Phenol, 2,4,6-
tris[(dimethylamino)methyl]- has not been tested in algae. Therefore algal growth inhibition testing
according to OECD guideline 201 is recommended.
2.4 Health Effects Data
2.4.1 Acute Health Effects
2.4.1.1 Acute Oral Toxicity
Groups of ten Sprague-Dawley rats (five male and five female) were orally administered undiluted
phenol, 2,4,6-tris[(dimethylamino)methyl]- at dose levels of 1333, 2000 and 3000 mg/kg body
weight. Surviving animals were observed daily post-dose for 14 days. All animals in the low dose
group survived. Three out of ten animals in the mid-dose group died. All animals in the high-dose
group died. All surviving animals appeared normal within three days or less of dosing, gained
weight, and the only findings seen at necropsy in the survivors were abnormalities of the non-
glandular stomach epithelium. Since this material is corrosive, the stomach findings were not
unusual. The oral LD
50
for phenol, 2,4,6-tris[(dimethylamino)methyl]- in rats was 2169 mg/kg body
weight [Ref. 11].
2.4.1.2 Summary of Acute Toxicological Effects
Phenol, 2,4,6-tris[(dimethylamino)methyl]- is practically non-toxic following a single oral exposure.
Scientifically reliable data exists for the SIDS acute toxicity endpoint. Additionally this material is
corrosive, therefore no additional acute toxicity testing is recommended.
2.4.2 Genetic Toxicology Effects
2.4.2.1 Bacterial Gene Mutation Assay
Phenol, 2,4,6-tris[(dimethylamino)methyl]- diluted in sterile water was examined for mutagenic
activity in a Salmonella typhimurium-Escherichia coli direct plate incorporation assay. The assay
was performed using S. typhimurium strains TA1535, TA1537, TA98, and TA100 and E. coli strain
WP2uvrA
-
over a dose range of 50 to 5,000 ug/plate in both the presence and absence of a
phenobarbitone/-naphthoflavone-induced rat-liver S9 metabolic activation system. OECD guideline
471 was followed. Phenol, 2,4,6-tris[(dimethylamino)methyl]- was not mutagenic under the test
conditions used in this bacterial assay. [Ref. 12]
2.4.2.2 I n Vitro Chromosomal Aberration Assay
Phenol, 2,4,6-tris[(dimethylamino)methyl]- has not been tested for chromosomal aberrations.
Phenol, 2,4,6-tris[(dimethylamino)methyl]- 4
2.4.2.3 Summary of Genetic Toxicology Effects
Phenol, 2,4,6-tris[(dimethylamino)methyl]- was not mutagenic when examined in a Salmonella
typhimurium-Escherichia coli direct plate incorporation assay according to OECD guideline 471.
Phenol, 2,4,6-tris[(dimethylamino)methyl]- has not been tested for chromosomal aberrations.
Therefore an in vitro chromosomal aberration test according to OECD guideline 473 is
recommended.
2.4.3 Repeated Dose Health Effects
2.4.3.1 Systemic Dermal Toxicity
Rats were exposed dermally to tris(dimethylaminomethyl)phenol at dose levels of 0, 5, 25, and 125
mg/kg/day, 5 days/week for 4 weeks. Treatment-related signs and symptoms included slight to
moderate excitability and/or hypertonicity in the 25- and 125-mg/kg, dose groups. Slight to
moderate erythema, occasionally accompanied by edema and necrosis, was observed in the 125-
mg/kg, dose group. Histopathology revealed moderate to marked hydropic change and slight
parakeratosis in the epidermis in the 125-mg/kg, dose group. Slight hydropic change without
parakeratosis was noted in the 25-mg/kg, dose group. The no observed effect level (NOEL) was 5
mg/kg/day [Ref. 13].
2.4.3.2 Reproductive and Developmental Toxicity
Phenol, 2,4,6-tris[(dimethylamino)methyl]- has not been tested for reproductive or developmental
effects.
2.4.3.3 Summary of Systemic, Reproductive and Developmental Toxicity Effects
Phenol, 2,4,6-tris[(dimethylamino)methyl]- has been evaluated for repeated dose effects via the
dermal route of exposure. Due to the corrosive nature of the material, the dose levels employed
were relatively low and the clinical and pathological findings were limited to the site of exposure. It
is therefore unclear whether phenol, 2,4,6-tris[(dimethylamino)methyl]- would be systemically toxic
via oral exposure where a higher dose may be feasible.
Phenol, 2,4,6-tris[(dimethylamino)methyl]- has not been tested for reproductive or developmental
effects. Therefore a combined oral repeat dose/repro-screening test according to OECD guideline
422 is recommended.
3.0 CONCLUSIONS
The majority of the data needed to meet the requirements of the HPV program are available and of high
quality for phenol, 2,4,6-tris[(dimethylamino)methyl]-. Data for several endpoints are not currently
available, therefore additional studies have been recommended to assess the hazards of this chemical.
Table 1 shows the studies that exist for phenol, 2,4,6-tris[(dimethylamino)methyl]- and t he data that still
need to be developed.
Phenol, 2,4,6-tris[(dimethylamino)methyl]- 5
TABLE 1: HPV DATA REQUIREMENTS/CRITICAL STUDIES: Phenol, 2,4,6-tris[(dimethylamino)methyl]-
HPV Data Category Test Endpoint Acceptable Data
Reference (Klimisch Rating)
Data to be Generated
Melting Point 1 (1) No
Physical and
Chemical Properties
Boiling Point 2 (1) No
Vapor Pressure 3 (1) No
Partition Coefficient 4 (1) No
Water Solubility 5 (1) No
Photodegradation 6 (2) No
Environmental Fate
and Pathways
Hydrolysis NA No
Biodegradation 7 (1) No
Transport/Distribution 8 (2) No
Acute toxicity to Fish
9 (2)
No
Ecotoxicity
Acute toxicity to Aquatic
Invertebrates
10 (2)
No
Toxicity to Aquatic Plants No Yes
Acute toxicity
11 (1)
No
Repeated Dose
13 (2)
Yes
Genetic
Gene Mutation 12 (1)
No
Human Health Effects
Toxicity Chromosome
Aberration
No Yes
Reproductive Toxicity
No
Yes
Developmental Toxicity
No
Yes
Notes:
Data listed are cross-referenced to a Robust Summary report [i.e. 1 (2)]; which identifies the reference number and
Klimisch Rating ( ).
NA= Not Applicable
Phenol, 2,4,6-tris[(dimethylamino)methyl]- 6
4.0 REFERENCES
1. Melting Point: Air Products and Chemicals, Inc. (EXT-03/043). Phenol, 2,4,6-tris[(dimethylamino)methyl]-:
Determination of General Physico-Chemical Properties. Testing Facility: Safepharm Laboratories Ltd.,
Shardlow Derbyshire, UK. Study year: 2003. Klimisch = 1
2. Boiling Point: Air Products and Chemicals, Inc. (EXT-03/043). Phenol, 2,4,6-tris[(dimethylamino)methyl]-:
Determination of General Physico-Chemical Properties. Testing Facility: Safepharm Laboratories Ltd.,
Shardlow Derbyshire, UK. Study year: 2003. Klimisch = 1
3. Vapor Pressure: Air Products and Chemicals, Inc. (EXT-03/057). Phenol, 2,4,6-
tris[(dimethylamino)methyl]-: Determination of the Vapor Pressure (OPPTS 830.7950). Safepharm
Laboratories Ltd., Shardlow Derbyshire, UK. Study year: 2003. Klimisch = 1
4. Partition Coefficient: Air Products and Chemicals, Inc. (EXT-03/043). Phenol, 2,4,6-
tris[(dimethylamino)methyl]-: Determination of General Physico-Chemical Properties. Testing Facility:
Safepharm Laboratories Ltd., Shardlow Derbyshire, UK. Study year: 2003. Klimisch = 1
5. Water Solubility: Air Products and Chemicals, Inc. (EXT-03/043). Phenol, 2,4,6-
tris[(dimethylamino)methyl]-: Determination of General Physico-Chemical Properties. Testing Facility:
Safepharm Laboratories Ltd., Shardlow Derbyshire, UK. Study year: 2003. Klimisch = 1
6. Photodegradation: Estimation Programs Interface for Microsoft Windows (EPIWIN V3.10, U.S.
Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, D.C.)
Atmospheric Oxidation Program (v1.90). Klimisch = 2
7. Biodegradation: Air Products and Chemicals, Inc. (EXT-99/104). Ancamine K54: Assessment of Ready
Biodegradability: Closed Bottle Test. Testing Facility: Safepharm Laboratories Ltd., Shardlow Derbyshire,
UK. Study year: 1996. Klimisch = 1
8. Transport/Distribution: Estimation Programs Interface for Microsoft Windows (EPIWIN V3.10, U.S.
Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, D.C.) Level III
Fugacity Model. Klimisch = 2
9. Acute Toxicity to Fish: Air Products and Chemicals, Inc. (EXT-99/034). Acute Toxicity of DMP-30 to Carp
(Cyprinus carpio), Rainbow Trout (Salmo gairdneri), Mud Crab (Neopanope texana), and Grass Shrimp
(Palaemonetes vulgaris). Testing Facility: Bionomics, Inc., Wareham, Massachussetts, USA . Study year:
1973. Klimisch = 2
10. Acute Toxicity to Aquatic Invertebrates: Air Products and Chemicals, Inc. (EXT-99/034). Acute Toxicity of
DMP-30 to Carp (Cyprinus carpio), Rainbow Trout (Salmo gairdneri), Mud Crab (Neopanope texana), and
Grass Shrimp (Palaemonetes vulgaris). Testing Facility: Bionomics, Inc., Wareham, Massachussetts, USA .
Study year: 1973. Klimisch = 2
11. Acute Oral Toxicity: Air Products and Chemicals, Inc. (EXT-92/042). Ancamine K54 (BX352): Acute Oral
Toxicity Test in the Rat. Testing Facility: Safepharm Laboratories Ltd., Shardlow Derbyshire, UK. Study
year: 1992. Klimisch = 1
12. Gene Mutation: Air Products and Chemicals, Inc. (EXT-03/071). Phenol, 2,4,6-Tris[(dimethylamino)
methyl]-: Reverse Mutation Assay Ames Test Using Salmonella typhimurium and Escherichia coli (OECD
471). Testing Facility: SafePharm Laboratory, Shardlow, Derbyshire, UK. Study year: 2003. Klimisch = 1
13. Systemic Dermal Toxicity: Initial Submission: Final Report - TK 10433 - 28-Days Dermal Toxicity Study in
Rats, EPA/OTS Doc # 88-920007287. Study year: 1986. Klimisch = 2
Phenol, 2,4,6-tris[(dimethylamino)methyl]- 7